Low-grade serous ovarian cancer at a crossroad: bridging biology and clinical practice

Low-grade serous ovarian cancer (LGSOC) represents a rare but clinically challenging subtype of epithelial ovarian cancer, accounting for approximately 5–10% of cases. (1). The molecular profile of LGSOC is characterized by mitogen-activated protein kinase (MAPK) pathway activation, usually through KRAS or BRAF mutations, whereas TP53 alterations are rare, in contrast to high-grade serous carcinomas (2). Despite its relatively indolent course, LGSOC is characterized by poor sensitivity to cytotoxic chemotherapy and limited benefit from hormonal therapies, leaving patients with few effective options once the disease recurs (3).

In early-stage disease, surgery remains the cornerstone of treatment. In the adjuvant setting, current guidelines recommend platinum-based chemotherapy for early-stage LGSOC starting from stage IC, although the evidence is largely extrapolated from studies in high-grade tumors. The benefit of adjuvant chemotherapy in LGSOC remains uncertain, and omission may be reasonable for completely staged stage IA–IB cases (4). Given the hormone receptor positivity in most tumors, adjuvant endocrine therapy, primarily supported by retrospective studies, has been increasingly adopted as a maintenance approach, particularly for patients with residual disease or high-risk features. In the pivotal MD Anderson series, hormonal maintenance therapy (HMT) after platinum-based chemotherapy significantly prolonged progression-free survival (PFS) (median 64.9 vs. 26.4 months for observation; P<0.001) (3). Although retrospective in nature, this evidence has been practice-changing in LGSOC and provides a strong rationale for further investigation in a randomized setting. This need is currently being prospectively evaluated in the phase III NRG-GY019 trial, which compares adjuvant endocrine therapy with standard platinum-based chemotherapy in stage II–IV LGSOC (5).

In the context of disease recurrence, secondary cytoreductive surgery should be considered whenever complete resection is feasible (4), given that traditional chemotherapy approaches have consistently shown limited benefit, with objective response rates (ORRs) ranging from 4% to 13% and median PFS of approximately 4–6 months (1,3). The recognition of poor chemosensitivity has led to a paradigm shift exploring endocrine therapy and other targeted approaches. Currently, targeted therapies such as BRAF inhibitors, CDK4/6 inhibitors, and mitogen-activated protein kinase kinase (MEK) inhibitors, as well as antiangiogenic agents like bevacizumab, have been increasingly adopted in clinical practice for this challenging scenario (2). Combination strategies—pairing hormonal blockade with agents targeting the MAPK pathway—represent promising avenues toward individualized therapy for this indolent but therapeutically challenging disease (6). In the context of relapsed disease, the recently reported ENGOT-OV60/GOG-3052/RAMP 201 trial represents a meaningful advance for this underserved population. This phase II study evaluated avutometinib, a first-in-class BRAF/MEK clamp, in combination with defactinib, a focal adhesion kinase (FAK) inhibitor, in women with recurrent LGSOC after ≥1 prior systemic therapy, including prior platinum. The scientific rationale is compelling: LGSOC is frequently driven by MAPK pathway alterations, most commonly KRAS (35–40%), NRAS (10–15%), or BRAF (5–15%) mutations (2,3). While MEK inhibitors have demonstrated activity in this setting, responses have often lacked durability, in part due to adaptive resistance mediated through FAK signaling. The dual inhibition of MEK and FAK therefore offers a biologically rational strategy to overcome these resistance mechanisms (7). In part A, patients were randomized to receive either avutometinib monotherapy or the combination regimen. Part B expanded enrollment in both arms, and part C focused exclusively on the combination after an interim analysis identified it as the preferred (“go-forward”) approach. Part D assessed a lower starting dose of avutometinib with defactinib. The primary efficacy and safety analyses, ORR confirmed by blinded independent central review, were conducted across parts A through C. Patients were heavily pretreated, with a median of three prior systemic regimens. Nearly all had received platinum-based chemotherapy, most had been exposed to hormonal therapy (86%), roughly half to bevacizumab (51%), and about 1 in 5 to a prior MEK inhibitor (22%) (7). The combination of avutometinib and defactinib achieved an ORR of 31% vs. 17% in the monotherapy group. The disease control rate (DCR) was 88% among 115 patients, with responses more pronounced in KRAS-mutant tumors (ORR 44% vs. 17% in wild-type). Median PFS reached 12.9 months overall and 22.0 months in the KRAS-mutant subgroup, while the median duration of response was 31 months, highlighting the potential for durable benefit. Importantly, the regimen was generally well tolerated: the most frequent grade ≥3 adverse events (AEs) were elevated creatine phosphokinase (CPK) (24%), diarrhea (8%), and anemia (5%) (7). Although a significant proportion of patients experienced grade 1–2 AEs, these were effectively managed with dose interruptions in 56% and dose reductions in 10% of cases, resulting in treatment discontinuation in only 10% of patients. Cutaneous toxicity, ocular events, and elevations in CPK represent the main safety concerns associated with the drug combination.

These results compare favorably with prior studies of MEK inhibitors. In the randomized phase II/III GOG-281/LOGS trial, trametinib significantly outperformed chemotherapy, achieving an ORR of 26% vs. 6%, and improving median PFS to 13.0 months compared with 7.2 months [hazard ratio (HR), 0.48; P<0.001], establishing trametinib as a treatment option in this disease (8). Among patients with somatic data available, 33% had activating mutations in KRAS, BRAF, or NRAS. Notably, despite this mutation status, the observed treatment effect on PFS favored trametinib in both mutation-positive [HR, 0.55; 95% confidence interval (CI): 0.28–1.07] and mutation-negative patients (HR, 0.64; 95% CI: 0.39–1.03) (8). A key innovation of RAMP 201 was the prospective stratification by KRAS status, which allowed the demonstration of a biomarker-driven benefit: patients with KRAS mutations achieved superior outcomes in both ORR and PFS compared to KRAS wild-type. This represents a significant step toward precision oncology in LGSOC, supporting the rationale for biomarker-based patient selection in future clinical practice. By contrast, the MILO/ENGOT-ov11 trial of binimetinib failed to meet its primary endpoint, with a median PFS of 9.1 months vs. 10.6 months for physician’s choice chemotherapy (HR, 1.21), and an ORR of 16% vs. 13%, leading to early termination of the study (9). These results highlight the heterogeneity of outcomes with MEK inhibition and the unmet need for more effective regimens. Against this backdrop, the RAMP 201 results stand out for both the magnitude and durability of responses, particularly in the biomarker-defined KRAS-mutant subgroup. The RAMP 201 is not without limitations. The absence of a standard-of-care comparator arm limits definitive conclusions regarding relative efficacy, and the modest sample size warrants caution in interpretation. Moreover, long-term survival outcomes remain to be established. These questions are now being addressed in the ongoing randomized phase III RAMP 301 trial, which will compare avutometinib plus defactinib against investigator’s choice of therapy (7).

Another treatment option for patients with BRAF V600E-mutated tumors is the combination of dabrafenib and trametinib, supported by the tumor-agnostic approval of this regimen. The current evidence is limited to case reports describing sustained responses in patients with BRAF V600E-mutated LGSOC, as well as the inclusion of ovarian cancer cases within broader basket trials, which collectively reinforce the tumor-agnostic applicability of BRAF/MEK inhibition (10,11).

Paradoxically, despite advances in biological understanding of LGSOC, including its hormone receptor expression, MAPK pathway alterations, indolent clinical behavior, and the consistently poor results achieved with chemotherapy, cytotoxic regimens remain the backbone of adjuvant and first-line treatment. Although designing clinical trials for rare diseases remains challenging, it is essential to better define the role of targeted therapies in the first-line setting, as chemotherapy appears to provide limited benefit in LGSOC.

Several ongoing clinical trials aim to redefine standard treatment approaches. The phase III NRG-GY019 (NCT04095364) and LEPRE (NCT05601700) trials are evaluating endocrine therapy as adjuvant and first-line option for stage II–IV disease, challenging the conventional role of chemotherapy. The BOUQUET trial (NCT04931342) is assessing the efficacy and safety of biomarker-driven therapies in patients with persistent or recurrent rare epithelial ovarian tumors, specifically those with platinum-resistant disease, defined as progression during or within six months of the last platinum regimen. This umbrella study includes multiple targeted therapy arms, such as ipatasertib for PI3K-mutated tumors and trastuzumab emtansine for HER2-overexpressing tumors. In addition, the phase II CHAMELEON trial (NCT06394804) is testing the combination of avutometinib, defactinib, and letrozole in patients with newly diagnosed or incompletely resectable LGSOC, further exploring the potential of combining targeted agents with endocrine therapy in this setting, and likely paving the way for a redefinition of first-line standards.

As the field moves toward biomarker-guided therapy, the challenge lies not only in validating novel combinations but in ensuring that the biological distinctiveness of LGSOC is finally reflected in its standard of care.

Acknowledgments

None

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Gynecology and Pelvic Medicine. The article has undergone external peer review.

Peer Review File: Available at https://gpm.amegroups.com/article/view/10.21037/gpm-2025-1-54/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://gpm.amegroups.com/article/view/10.21037/gpm-2025-1-54/coif). M.L.M.J. received honoraria from GSK and AstraZeneca. D.J.P. received honoraria from Novartis, GSK, Gilead. M.P.A. received honoraria from AstraZeneca and GSK. A.N.R. received MSD grant to study focus HPV vaccination; honoraria from Roche, MSD, AstraZeneca, ESAI, GSK, Daiichi, Novartis, Pfizer Lilly E Gilead; support for attending meetings and travel from Roche, MSD, Astrazenca, Daiichi, GSK; payment for participation in Advisory Board from Scientific Ad Board, Roche, MSD, Astrazeneca, ESAI, GSK, Novartis, Pfizer, Lilly E Gilead. A.N.R. is director strategic planning Brazilian Group of Gynecology Oncology president SBOC (Brazilian Society of Medical Oncology), chair gynecology oncology. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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